All About Neuroblastoma

Neha Vapiwala, MD,John P. Plastaras, MD, PhD, and Christine Hill-Kayser, MD The Abramson Cancer Center of the University of Pennsylvania Last Modified: January 17, 2012

What Is Neuroblastoma?

Neuroblastoma is a tumor of nerve tissue that, under the microscope, looks like "small, round, blue" cells.. Neuroblastoma most commonly arises in the abdomen (from the adrenal glands, which sit on top of the kidneys), but can also start in the neck, chest, or pelvis. Unfortunately, regardless of where it starts, by the time it is diagnosed the cancer has often spread (metastasized) throughout the body, usually to the lymph nodes, liver, lungs, bones, and bone marrow.

Who Gets Neuroblastoma?

Neuroblastoma is the most common non-brain solid pediatric tumor. It is mainly a tumor of infancy and early childhood. In fact, the majority of neuroblastoma cases are diagnosed in children younger than 5 years of age. It is rarely found in children older than 10 years. Actually, the tumor is often present at birth but not detected until later, when it has grown to a noticeable size and/or starts to cause symptoms.

What Are The Symptoms?

The typical symptoms of neuroblastoma are related to the location of the tumor. They occur when the tumor grows and exerts pressure on surrounding organs or within bone. An abdominal tumor may cause abdominal pain, nausea, vomiting, and/or constipation. Involvement of the bones and bone marrow can cause diffuse bony pain or pain in a specific bone or joint. Parents of young children who cannot yet speak may note that a child with neuroblastoma has started refusing to walk; this may be due to pain with walking. A trademark sign of orbit involvement by tumor cells is a young child with bulging eyes and dark circles under the eyes ("raccoon eyes"). General findings may include fever, weight loss, and anemia. Occasionally, neuroblastoma tumors may release hormones and neurotransmitters that can cause high blood pressure, severe watery diarrhea, jerky muscle spasms, and/or uncontrollable eye movement (a syndrome called "opsoclonus/myoclonus" or "dancing eyes/dancing feet."

How Is It Diagnosed?

There are a few reports of neuroblastoma cases that are incidentally detected before birth by fetal ultrasound. Such cases are exceedingly rare; much more commonly, neuroblastoma is diagnosed after symptoms such as the above are noted. In such a situation, the child should be examined by the pediatrician, who will perform a careful physical examination and typically order some laboratory tests and imaging studies. The urine can be tested for catecholamines, which are special hormones normally produced only by the adrenal gland but are also produced by 90% of neuroblastomas. A computed tomographic (CT) scan or magnetic resonance imaging (MRI) scan may also be ordered.

Ultimately, a definitive diagnosis of neuroblastoma requires a tissue sample, and thus a tissue biopsy from the tumor and/or bone marrow is obtained. A biopsy is a small sample of the suspected tumor tissue that is surgically removed and examined under a microscope. It can sometimes be done by making a small hole and using a needle to extract a sample of the tissue.

Once the diagnosis of neuroblastoma is made, a bone marrow biopsy and a bone scan is done to see if the tumor has spread. Another special test for neuroblastoma is the I-123 MIBG scan, which is a nuclear medicine study. It is uses a radioactive tracer (metaiodobenzylguanidine, or MIBG) that is specifically taken up by neuroblastoma cells and may detect hidden deposits of tumor using a gamma camera.

How Is Neuroblastoma Staged?

For the purposes of understanding the full spectrum of neuroblastoma and extent of disease, think of neuroblastoma as falling into one of the following categories:

Localized and resectable

Cancer is confined to the site of origin with NO evidence of spread

Cancer can be surgically removed

Localized and unresectable

Cancer is confined to the site of origin

BUT the cancer cannot be completely removed surgically Regional

Regional

Cancer has extended beyond the site of origin to regional lymph nodes and/or surrounding organs or tissues, but has not spread to distant parts

Disseminated

Cancer has spread from the site of origin to distant lymph nodes, bone, liver, skin, bone marrow, and/or other organs (except as defined for stage 4S)

A special circumstance: Stage 4S

Stage 4S neuroblastoma is also called "special" neuroblastoma because it is treated differently. The cancer is localized, with spread limited to liver, skin, and/or, to a very limited extent, bone marrow, and occurs only in children 1 year of age or less.

Recurrent

Recurrent neuroblastoma means that the cancer has come back (recurred) or continued to spread (progressed) after it was treated. It may come back in the original site or in another part of the body.

The actual medical staging system used by healthcare professionals is The International Neuroblastoma Staging System (INSS), which has been in use since the 1990's. The stages are:

Stage 1

The cancer is on one side of the body and is localized (hasn't spread). All visible tumor is totally removed by surgery. Examination of the tumor's edges under the microscope may show some cancer cells. Lymph nodes enclosed within the tumor may contain neuroblastoma cells, but lymph nodes outside of the tumor should be free of cancer.

Stage 2A

The cancer is on one side of the body and is localized, but because of its size, location, or relationship to other organs, it cannot be totally removed by surgery. Lymph nodes enclosed within the tumor may contain neuroblastoma cells, but lymph nodes outside of the tumor should be free of cancer.

Stage 2B

The cancer is on one side of the body, is localized, and may or may not be able to be totally removed by surgery. Lymph nodes outside the tumor contain neuroblastoma cells, but the cancer has not spread to lymph nodes on the other side of the body.

Stage 3

The cancer cannot be completely removed by surgery.

It has crossed the midline to the other side of the body. It may or may not have spread to nearby lymph nodes. OR

It is on one side of the body but has spread to lymph nodes that are relatively nearby but on the other side of the body. OR

It is in the middle of the body and growing toward both sides and cannot be completely removed by surgery.

Stage 4

The cancer has spread to distant sites such as lymph nodes, bone, liver, skin, bone marrow, or other organs. But the child does not meet criteria for stage 4S.

Stage 4S (also called "special" neuroblastoma)

The child is less than 1 year old. The cancer is on one side of the body and is localized. It may have spread to lymph nodes on the same side of the body, but not to nodes on the other side. Neuroblastoma has spread to the liver, skin, and/or the bone marrow. However, no greater than 10% of marrow cells may be cancerous, and imaging studies should not show bone damage.

Recurrent

The cancer has come back (recurred) after it was previously treated. It may come back in the area where it first started or in another part of the body.

What Is The Prognosis Of A Child With Neuroblastoma?

Generally speaking, the chance of recovery (prognosis) for any given patient with neuroblastoma depends on the child's age at diagnosis, the location of the tumor, the appearance of the tumor cells under a microscope, and, of course, the stage of disease.

Specifically, the following features of cancer tend to predict the child's likelihood of cure better than the prediction using only disease stage:

Tumor grade - Tumor grade is based on appearance of neuroblastoma cells under the microscope, which include estimates of proliferative activity (proportion of actively dividing cells) and ratios of very immature cells to more mature, normal nerve tissue-resembling cells.

DNA ploidy - Ploidy refers to the amount of DNA in each cell, aka ploidy, measured by special lab techniques like flow cytometry or imaging cytometry. Normal cells are diploid. Neuroblastoma cells with increased amounts of DNA are termed hyperdiploid, and in infants, hyperdiploid cells are associated with earlier stages of disease, better response to therapy, and thus a generally better outcome than diploid cells.

Cytogenetics -The cytogenetic make up of a cell refers to the number of chromosomes the cell as counted under a microscope, with notation of any abnormalities. Normal cells have 46 chromosomes (2 sets of 23), which are made of DNA and protein. Neuroblastomas with normal chromosome numbers tend to be more aggressive than those with extra chromosomes. Tumors that are missing certain parts of chromosomes 1 or 11 (known as "1p deletions" or "11q deletions") have a worse prognosis. Neuroblastomas with too many copies of the N-MYC oncogene (amplification) tend to grow more quickly and are associated with a worse prognosis than children without the amplification.

Oncogene amplifications - Oncogenes are regions of DNA that are vital in controlling cell growth.Changes within those genes can make cells grow and divide too quickly, which is what cancer cells do.

High levels of ferritin, a chemical that is important for normal iron metabolism, may be associated with a worse

Increased levels of neuron-specific enolase (NSE) and lactate dehydrogenase (LDH) may also predict a worse outlook

What Are The Neuroblastoma Risk Groups?

Using many of the above prognostic factors in concert, three different risk groups can be created. Children with neuroblastoma can be assigned to the appropriate risk group in order to help guide treatment:

Low Risk

Stage 1 (all)

Stage 2A and 2B, except for child age 1 year or older with N-MYC amplification and unfavorable histology Stage 4S, no N-MYC amplification, favorable histology, and hyperdiploid

High Risk

Stage 2A and 2B, age 1 year or older, N-MYC amplification, and unfavorable histology

Stage 3, N-MYC amplification

Stage 3, age 1 year or older, no N-MYC amplification, and unfavorable histology

Stage 4, age 1 year or older

Stage 4, age <1 year, N-MYC amplification

Stage 4S, N-MYC amplification

What Are The Recommended Treatment Options?

Because neuroblastoma is relatively rare, it is best treated at a facility by clinicians who have experience. If possible, children should be treated on a cooperative group clinical protocol.

Low Risk

Children at low risk usually only require surgery, as this should remove all visible and microscopic tumor from the body in this group of patients. However, for those few children that might be symptomatic, chemotherapy or radiotherapy may be required to control the symptoms.

Intermediate Risk

Children at intermediate risk should receive 4 to 8 cycles (1 or 2 courses) of chemotherapy before or after surgery to control the disease, usually given as a combination of agents. The typical drugs used in neuroblastoma include: cyclophosphamide, doxorubicin, cisplatin, carboplatin, and etoposide. "Second look" surgery (repeat surgery after chemotherapy and/or radiation therapy to check the results of therapy and to remove any remaining cancerous tissue if possible) or radiation therapy may or may not be needed.

High Risk

Children at high risk require very intensive chemotherapy, which can necessitate bone marrow or peripheral stem cell transplant(s) for marrow support. Total body irradiation has sometimes been used as part of bone marrow transplant, but it is not always used. Surgery and/or localized radiation therapy may be part of the treatment. Biological agents such as 13-cis retinoic acid and antibody treatments may also be offered, particularly to children who are being treated on cooperative group protocols. MIBG, which is often used as part of the diagnosis and staging for neuroblastoma (see above) can also sometimes be used therapeutically for treatment of refractory or progressive disease.

Recurrence

Unfortunately, some children will have disease recurrence after initial therapy. Treatment options at this point will depend on many factors, including the initial risk group and where in the body the cancer came back. Chemotherapy, surgery, radiation therapy, or even simple observation may be appropriate, depending on the circumstances.

Has Proton Radiotherapy Been Used for Neuroblastoma?

Some children with neuroblastoma may be good candidates for proton therapy. Proton therapy has been used for neuroblastoma at some specialized centers, including the Children's Hospital of Philadelphia and the Massachusetts General Hospital. The decision of whether proton therapy is the best treatment for a certain patient must be made by the team of physicians caring for the child, as well as a team from a proton referral center.

What Are The Results Of Treatment?

The 5-year survival rate refers to the percentage of patients who live at least 5 years after their cancer is diagnosed. These rates are for treated neuroblastoma.